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Editorial
 
Tumor Necrosis Factor Inhibition in the Treatment of Refractory Sarcoidosis: Slaying the Dragon?
NADERA J. SWEISS, MD,
Section of Rheumatology, University of Chicago, Chicago, Illinois; ROBERT P. BAUGHMAN, MD, Interstitial Lung Disease and Sarcoidosis Clinic, Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA Address reprint requests to Dr. R.P. Baughman, 1001 Holmes, University of Cincinnati Medical Center, Eden Avenue, Cincinnati, OH 45267-0565. Saint George, the symbol for the World Association for Sarcoidosis and Other Granulomatous Diseases (WASOG), has long been known as the "dragon slayer"; his pictures show a brave knight in battle with a fierce dragon; sometimes, a beautiful princess is present. Saint George is fighting an evil monster with multiple heads to protect God's truth. Sarcoidosis is a chronic granulomatous disease of unknown etiology that affects every organ system and has various presentations, like a dragon with multiple heads1. The treatments for sarcoidosis represent different types of swords. Glucocorticoids are a broadsword, inhibiting many of the inflammatory pathways activated in the disease. Methotrexate, thalidomide, and chloroquine have a more limited antiinflammatory effect, mostly directed towards the activated macrophage2. And while the US Food and Drug Administration has not approved a therapy for sarcoidosis, several have become standard therapy for a subset of sarcoidosis patients1. Granulomas are created by macrophages, epithelioid cells, giant cells, and T cells. Increased tumor necrosis factor-a (TNF-a) secretion by alveolar macrophages is found in patients who have progressive pulmonary disease3. Another feature of sarcoidosis is anergy. A recent study by Miyara, et al demonstrated that CD4+CD25brightFoxP3+ cells accumulated at the periphery of sarcoid granulomas4. These T regulatory cells have potent antiproliferative activity, including the suppression of TNF, and may account for anergy. It has been suggested that the compartmentalization of the inflammatory response can explain why some areas such as the lung have intense inflammation, with a T cell influx, while other areas, such as the peripheral blood, can have lymphopenia. The immune response is variable in different organs of the same sarcoidosis patient. The clinical response to sarcoidosis is also variable. Some patients have an acute, self-limited form of the disease: within 2 to 5 years, their disease resolves, with no need for further therapy. In the United States, this represents about 75% of sarcoidosis patients5. In a subgroup of patients the sarcoidosis is chronic, requiring years of treatment. Treatments targeting TNF2 are used in these chronic patients. Specific inhibition of TNF using the biological agents etanercept, infliximab, or adalimumab has been effective in the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and various inflammatory conditions6. Infliximab but not etanercept is effective in treating Crohn's disease, a granulomatous process. Etanercept was also not found to be effective as an additional agent in treating patients with Wegener's granulomatosis. Infliximab has been extremely effective for some cases of refractory sarcoidosis7. A multicenter, randomized, double-blind, placebo-controlled study of 138 patients with chronic pulmonary sarcoidosis treated with infliximab showed a statistically significant improvement in forced vital capacity after 24 weeks of therapy, the primary endpoint of the study8. Adalimumab has been used with success in some patients with therapy-resistant sarcoidosis. Etanercept was found to be effective in occasional case reports of patients with sarcoidosis. However, in a randomized trial of ocular sarcoidosis, etanercept was no better than placebo9. Disease heterogeneity and differences in pharmacokinetics, pharmacodynamics, and mechanisms of action may account for these effects10. Reverse-signaling by transmembrane TNF in response to infliximab and adalimumab, but not etanercept, might also influence the therapeutic response. Also, infliximab, but not etanercept, leads to cell lysis of active inflammatory cells releasing TNF in patients with Crohn's disease. In this month's issue of The Journal, Sturfelt, et al report a case of neurosarcoidosis occurring in a patient with rheumatoid arthritis treated with infliximab and methotrexate11. This follows several other reports of cases of sarcoidosis-like disease during treatment with etanercept12-14 or infliximab15. The time course of development varied from 6 months to 5 years. Development of sarcoidosis months after initiation of therapy argues against a simple drug allergy as the cause of the granulomas. Most cases occurred in patients receiving etanercept for rheumatoid arthritis, while one occurred secondary to infliximab for ankylosing spondylitis. The mostly European cases presented with mediastinal adenopathy, skin manifestations, and/or mild pulmonary symptoms. Signs and symptoms resolved after discontinuation of therapy. Since the etiology of sarcoidosis is unknown, diagnosis is always in question. However, there is consensus on a diagnosis of sarcoidosis if granulomas are present in 2 or more organs and granulomas have been confirmed by histology in at least one area. However, other causes for granulomas should first be ruled out1. In the cases reported here of anti-TNF therapy-associated sarcoidosis, the authors were careful to exclude other causes of granulomatous diseases, especially tuberculosis. The use of an anti-TNF agent may allow infection or reactivation of a less virulent mycobacterial or fungal organism, leading to a granulomatous response. Such an organism may be difficult to detect with standard methodology. We are not aware of any detailed, broad-based polymerase chain reaction (PCR) evaluation of granulomas from patients with anti-TNF-associated sarcoidosis. There are reports using PCR to detect nontuberculous mycobacteria in some patients with sarcoidosis-like condition16. These questions remain the subject of ongoing investigations. TNF inhibition has been associated with induction or worsening of various autoimmune diseases, systemic lupus, vasculitis, interstitial lung disease, psoriasis, and Crohn's disease17. New onset or severe exacerbation of psoriasis has been described as a rare complication of TNF-a inhibitor therapy. Increased production of interferon-a in TNF-a inhibitor-associated psoriasis has been proposed as a pathophysiologic explanation for this reaction18. Treatment of hepatitis C with recombinant interferon-a has been associated with development of sarcoidosis19. TNF is a factor in the initiation and maintenance of granulomas. TNF knockout mice exposed to Mycobacterium do form granulomas, but the granulomas are smaller and more likely to become apoptotic20. This is similar to the resolution of granulomas in the acute, self-limited form of sarcoidosis1,5. In addition, T regulatory cells, which suppress TNF release, are found on the periphery of granulomas in sarcoidosis patients with acute disease4; however, the exact role of Treg cells in the pathogenesis of sarcoid granulomas remains unknown. In addition, anti-TNF therapy does not lead to continuous total suppression of TNF. Changes in the level of TNF may allow granulomas to form. Rebound, higher levels of TNF may be encountered even with anti-TNF therapy21. It is interesting to note that most case reports to date of sarcoidosis associated with anti-TNF therapy occurred in patients being treated with etanercept. The balance of the inflammatory response in sarcoidosis seems to be a key aspect of the variable nature of the clinical course of the disease1,2. While an initial manifestation of sarcoidosis is the formation of granulomas, it is the response to these granulomas that determines the clinical course of the patient. In most patients granulomas resolve over the following 2 to 5 years, with or without therapy5. In those with chronic disease, cytokines such as TNF and interleukin 8 seem to persist2,3. To date, sarcoidosis occurring during anti-TNF therapy appears to be self-limiting. Anti-TNF therapy has been used for chronic sarcoidosis. Patients with chronic disease have granulomas that are already well established and continue to worsen despite therapy7,8. Agents such as cyclosporine, which inhibit CD-4 function, have a limited role in these patients1. Not all patients with refractory sarcoidosis respond to anti-TNF therapy8. Therefore, it is not surprising that a single, targeted therapy may be associated with appearance of sarcoidosis. This might be the result of a "break through" of the disease, altered cytokine balance, increased interferon-a levels, rebound TNF secretion, or exposure to an infectious agent that stimulates the granulomatous process, or to a combination of these factors. While Saint George is usually shown brandishing a single sword to fight the dragon, the American Thoracic Society recommends several swords in order to target sarcoidosis-associated hypercalcemia, and cardiac, ocular, and neurologic sarcoidosis1. It is not clear which is the best sword to use and what is the best time to declare war on this dragon with multiple heads. Anti-TNF therapy may be able to slay a major part of the disease. However, as any gardener will tell you, pruning one part of the plant may allow another bud to grow. Therefore, constant monitoring of the patient remains crucial in the management of sarcoidosis. 2. Baughman RP, Iannuzzi M. Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs 2003;17:425-31. [MEDLINE] 3. Ziegenhagen MW, Rothe E, Zissel G, Muller-Quernheim J. Exaggerated TNF-alpha release of alveolar macrophages in corticosteroid resistant sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19:185-90. MEDLINE] 4. Miyara M, Amoura Z, Parizot C, et al. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006;203:359-70. [MEDLINE] 5. Baughman RP, Judson MA, Teirstein A, et al. Presenting characteristics as predictors of duration of treatment in sarcoidosis. QJM 2006;99:307-15. [MEDLINE] 6. Gartlehner G, Hansen RA, Jonas BL, Thieda P, Lohr KN. The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 2006;33:2398-408. [MEDLINE] 7. Sweiss NJ, Welsch MJ, Curran JJ, Ellman MH. Tumor necrosis factor inhibition as a novel treatment for refractory sarcoidosis. Arthritis Rheum 2005;53:788-91. [MEDLINE] 8. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795-802. [MEDLINE] 9. Baughman RP, Lower EE, Bradley DA, Raymond LA, Kaufman A. Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial. Chest 2005;128:1062-67. [MEDLINE] 10. Wallis RS, Ehlers S. Tumor necrosis factor and granuloma biology: explaining the differential infection risk of etanercept and infliximab. Semin Arthritis Rheum 2005;34 Suppl 1:34-8. 11. Sturfelt G, Christensson B, Bynke G, Saxne T. Neurosarcoidosis in a patient with rheumatoid arthritis during treatment with infliximab. (letter) J Rheumatol 2007;34:2313. 12. Kudrin A, Chilvers ER, Ginawi A, et al. Sarcoid-like granulomatous disease following etanercept treatment for RA. J Rheumatol 2007;34:648-9. [MEDLINE] 13. Verschueren K, Van Esche E, Verschueren P, Taelman V, Westhovens R. Development of sarcoidosis in etanercept-treated rheumatoid arthritis patients. Clin Rheumatol 2007 Mar 6; e pub. 14. Gonzalez-Lopez MA, Blanco R, Gonzalez-Vela MC, Fernandez-Llaca H, Rodriguez-Valverde V. Development of sarcoidosis during etanercept therapy. Arthritis Rheum 2006;55:817-20. [MEDLINE] 15. Almodovar R, Izquierdo M, Zarco P, Javier QF, Mazzucchelli R, Steen B. Pulmonary sarcoidosis in a patient with ankylosing spondylitis treated with infliximab. Clin Exp Rheumatol 2007;25:99-101. [MEDLINE] 16. Drake WP, Pei Z, Pride DT, Collins RD, Cover TL, Blaser MJ. Molecular analysis of sarcoidosis tissues for mycobacterium species DNA. Emerg Infect Dis 2002;8:1334-41. [MEDLINE] 17. Ramos-Casals M, Brito-Zeron P, Munoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine Baltimore 2007;86:242-51. [MEDLINE] 18. de Gannes GC, Ghoreishi M, Pope J, et al. Psoriasis and pustular dermatitis triggered by TNF-a inhibitors in patients with rheumatologic conditions. Arch Dermatol 2007;143:223-31. [MEDLINE] 19. Goldberg HJ, Fiedler D, Webb A, Jagirdar J, Hoyumpa AM, Peters J. Sarcoidosis after treatment with interferon-alpha: a case series and review of the literature. Respir Med 2006;100:2063-8. [MEDLINE] 20. Benini J, Ehlers EM, Ehlers S. Different types of pulmonary granuloma necrosis in immunocompetent vs. TNFRp55-gene-deficient mice aerogenically infected with highly virulent Mycobacterium avium. J Pathol 1999;189:127-37. [MEDLINE] 21. Bhatia A, Kast RE. Tumor necrosis factor (TNF) can paradoxically increase on etanercept treatment, occasionally contributing to TNF-mediated disease. J Rheumatol 2007;34:447-9. [MEDLINE]
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